A continuation of the study of hematopoietic aspects of aging is planned. Information already obtained indicates that although anemia is frequent in the elderly the etiology is not obvious. An overall reduction in hematopoiesis appears to be present with decreases in primitive hematopoietic stem cells. Further evidence of decreased reserve comes from animal studies in which minor stresses in the aged mouse are associated with major alterations in hematopoiesis. Furthermore a reduction in the ability of the aged mouse to respond to erythropoietic stimulation has been demonstrated. Long term culture of bone marrow has been developed as a model for the aging process. In future years a systematic approach aimed at defining the mechanism of decreased responsiveness of aged erythroid cells to stimulation by erythropoietin (Ep) will be developed. The subcellular abnormalities accounting for the defect will be defined by studies of receptor function, message translation and enzyme alteration when erythroid precursors are stimulated by Ep. In clinical studies particular attention will focus on granulopoiesis the aim being to define the effect of age on granulocyte turnover and function. In addition the possible role of nutritional deficiencies in the hematologic aspects of aging and their potential correctability by nutritional rehabiliation will be studied. Studies in the mice will complement those proposed in man and will primarily concentrate on the effects of age on the erythropoietic and myelopoietic response to stimulation or suppression. The use of long term bone marrow culture is ideally suited for the study of aging. Advantages include the multifactorial nature of cellular elements involved in normal hematopoietic cell production and the similarity between the in vitro culture system and in vivo hematopoiesis. Alteration in hematopoietic cell function, number and stromal activity as a function of the age of donor or the age of the culture will be determined. It is hoped that this program and study at the clinical, cellular and subcellular levels will more closely define the mechanisms of age related alterations in hematopoiesis.